@article{10.1172/jci.insight.85717, author = {David H. McMillan AND Jos L.J. van der Velden AND Karolyn G. Lahue AND Xi Qian AND Robert W. Schneider AND Martina S. Iberg AND James D. Nolin AND Sarah Abdalla AND Dylan T. Casey AND Kenneth D. Tew AND Danyelle M. Townsend AND Colin J. Henderson AND C. Roland Wolf AND Kelly J. Butnor AND Douglas J. Taatjes AND Ralph C. Budd AND Charles G. Irvin AND Albert van der Vliet AND Stevenson Flemer AND Vikas Anathy AND Yvonne M.W. Janssen-Heininger}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π}, year = {2016}, month = {6}, volume = {1}, url = {https://insight.jci.org/articles/view/85717}, abstract = {Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease characterized by excessive collagen production and fibrogenesis. Apoptosis in lung epithelial cells is critical in IPF pathogenesis, as heightened loss of these cells promotes fibroblast activation and remodeling. Changes in glutathione redox status have been reported in IPF patients. S-glutathionylation, the conjugation of glutathione to reactive cysteines, is catalyzed in part by glutathione-S-transferase π (GSTP). To date, no published information exists linking GSTP and IPF to our knowledge. We hypothesized that GSTP mediates lung fibrogenesis in part through FAS S-glutathionylation, a critical event in epithelial cell apoptosis. Our results demonstrate that GSTP immunoreactivity is increased in the lungs of IPF patients, notably within type II epithelial cells. The FAS-GSTP interaction was also increased in IPF lungs. Bleomycin- and AdTGFβ-induced increases in collagen content, α-SMA, FAS S-glutathionylation, and total protein S-glutathionylation were strongly attenuated in Gstp–/– mice. Oropharyngeal administration of the GSTP inhibitor, TLK117, at a time when fibrosis was already apparent, attenuated bleomycin- and AdTGFβ-induced remodeling, α-SMA, caspase activation, FAS S-glutathionylation, and total protein S-glutathionylation. GSTP is an important driver of protein S-glutathionylation and lung fibrosis, and GSTP inhibition via the airways may be a novel therapeutic strategy for the treatment of IPF.}, number = {8}, doi = {10.1172/jci.insight.85717}, url = {https://doi.org/10.1172/jci.insight.85717}, }